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<p>Drug-induced sleep disruption exacerbates addiction, causes long-term cognitive and emotional deficits, and becomes a key relapse trigger. However, despite the potent stimulant and hallucinogenic effects of synthetic cathinones, their impact on sleep–wake behaviors remains unstudied, and the role of striatal dopamine D2 receptors in mediating psychostimulant-induced arousal has yet to be identified. This study aimed to elucidate the mechanisms underlying N-ethylpentylone (NEP, a second-generation synthetic cathinone) induced alterations in sleep-wake behavior, specifically investigating the relative contributions of dopamine receptors (DARs) and serotonin receptors. Using the in vitro PRESTO-Tango assay, we characterized the interactions between NEP and various DARs, revealing that NEP produced the strongest β-arrestin recruitment response at dopamine D2 receptor (D2R) among the dopamine receptor subtypes tested. In vivo electroencephalogram/electromyogram (EEG/EMG) recordings in wild-type (WT) mice demonstrated that NEP dose-dependently promoted wakefulness and reduced non-rapid eye movement (NREM) sleep. This was accompanied by decreased θ-band and increased α-band power spectral density during wakefulness. Pharmacological blockade of D2R with haloperidol significantly attenuated NEP-induced wake promotion and partially reversed the aberrant EEG oscillations. Crucially, conditional knockout of D2R specifically in striatum markedly diminished the wake-promoting effects of NEP. In contrast, pharmacological blockade of the serotonin 2&#xa0;A receptor (5-HT2AR) with 1&#xa0;mg/kg MDL100907 did not significantly alter NEP-induced sleep–wake changes. Furthermore, immunofluorescence staining analysis confirmed that D2R blockade effectively reversed NEP-induced c-Fos expression in the striatum. Together, these findings demonstrated striatal D2R played a critical role in NEP-induced arousal.</p>

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Striatal Dopamine D2 Receptors Contribute to N-Ethylpentylone-Induced Arousal in Mice

  • 期刊论文

  • 发表日期：

    2026年8月3日

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  • Cheng-Teng Fan,
  • Jing-Ya Wang,
  • Hong Qian,
  • Shang-Qi Tang,
  • Zhi-Gang Zhong,
  • Yu-Rong Zhang,
  • Shui-Qing Zheng,
  • Mei-Hong Qiu,
  • Yu-Lan Rao,
  • Zhi-Ru Xu

摘要

Drug-induced sleep disruption exacerbates addiction, causes long-term cognitive and emotional deficits, and becomes a key relapse trigger. However, despite the potent stimulant and hallucinogenic effects of synthetic cathinones, their impact on sleep–wake behaviors remains unstudied, and the role of striatal dopamine D2 receptors in mediating psychostimulant-induced arousal has yet to be identified. This study aimed to elucidate the mechanisms underlying N-ethylpentylone (NEP, a second-generation synthetic cathinone) induced alterations in sleep-wake behavior, specifically investigating the relative contributions of dopamine receptors (DARs) and serotonin receptors. Using the in vitro PRESTO-Tango assay, we characterized the interactions between NEP and various DARs, revealing that NEP produced the strongest β-arrestin recruitment response at dopamine D2 receptor (D2R) among the dopamine receptor subtypes tested. In vivo electroencephalogram/electromyogram (EEG/EMG) recordings in wild-type (WT) mice demonstrated that NEP dose-dependently promoted wakefulness and reduced non-rapid eye movement (NREM) sleep. This was accompanied by decreased θ-band and increased α-band power spectral density during wakefulness. Pharmacological blockade of D2R with haloperidol significantly attenuated NEP-induced wake promotion and partially reversed the aberrant EEG oscillations. Crucially, conditional knockout of D2R specifically in striatum markedly diminished the wake-promoting effects of NEP. In contrast, pharmacological blockade of the serotonin 2 A receptor (5-HT2AR) with 1 mg/kg MDL100907 did not significantly alter NEP-induced sleep–wake changes. Furthermore, immunofluorescence staining analysis confirmed that D2R blockade effectively reversed NEP-induced c-Fos expression in the striatum. Together, these findings demonstrated striatal D2R played a critical role in NEP-induced arousal.